在视网膜变性过程中,TREM2 依赖性激活的小胶质细胞通过 PPARγ 和 CD36 保护感光细胞。

IF 8.1 1区 生物学 Q1 CELL BIOLOGY Cell Death & Disease Pub Date : 2024-08-26 DOI:10.1038/s41419-024-07002-z
Wenchuan Zhou, Jincan He, Guiyan Shen, Ya Liu, Peiquan Zhao, Jing Li
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引用次数: 0

摘要

视网膜变性是一系列具有破坏性的疾病,视力会逐渐丧失,往往会导致失明。对视网膜小胶质细胞的研究为阻止退化的进展提供了巨大的治疗潜力。本研究探讨了在视网膜变性过程中,活化的小胶质细胞在 TREM2 介导下发挥保护功能的机制。在C57BL/6 J(WT)和Trem2基因敲除(Trem2-/-)小鼠中建立了N-甲基-N-亚硝基脲(MNU)诱导的视网膜变性。我们发现,MNU处理会导致感光细胞凋亡和小胶质细胞浸润。在光感受器变性过程中,我们观察到与疾病相关的小胶质细胞特征基因明显上调。MNU治疗后,Trem2-/-小鼠的感光细胞死亡加剧,小胶质细胞迁移和吞噬能力下降,小胶质细胞PPARγ活化和CD36表达减少。药物激活 PPARγ 可促进小胶质细胞迁移,改善 MNU 处理的 Trem2-/- 小鼠的感光细胞变性,并恢复 CD36 的表达。抑制 CD36 的活性会加重 MNU 处理的 WT 小鼠的光感受器退化。我们的研究结果表明,在视网膜变性过程中,小胶质细胞的保护作用依赖于Trem2的表达,并通过激活PPARγ和随之上调CD36的表达来实现。我们的研究将TREM2信号传导与PPARγ激活联系起来,为治疗视网膜变性提供了潜在的治疗靶点。
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TREM2-dependent activation of microglial cell protects photoreceptor cell during retinal degeneration via PPARγ and CD36.

Retinal degeneration is a collection of devastating conditions with progressive loss of vision which often lead to blindness. Research on retinal microglial cells offers great therapeutic potential in deterring the progression of degeneration. This study explored the mechanisms underlying the TREM2-mediated protective function of activated microglial cells during retinal degeneration. N-methyl-N-nitrosourea (MNU)-induced retinal degeneration was established in C57BL/6 J (WT) and Trem2 knockout (Trem2-/-) mice. We discovered that MNU treatment led to the concurrent processes of photoreceptor apoptosis and microglia infiltration. A significant upregulation of disease-associated microglia signature genes was observed during photoreceptor degeneration. Following MNU treatment, Trem2-/- mice showed exacerbated photoreceptor cell death, decreased microglia migration and phagocytosis, reduced microglial PPARγ activation and CD36 expression. Pharmaceutical activation of PPARγ promoted microglial migration, ameliorated photoreceptor degeneration and restored CD36 expression in MNU-treated Trem2-/- mice. Inhibition of CD36 activity worsened photoreceptor degeneration in MNU-treated WT mice. Our findings suggested that the protective effect of microglia during retinal degeneration was dependent on Trem2 expression and carried out via the activation of PPARγ and the consequent upregulation of CD36 expression. Our study linked TREM2 signaling with PPARγ activation, and provided a potential therapeutic target for the management of retinal degeneration.

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来源期刊
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
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